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Structural basis of human 20S proteasome biogenesis

Author

Listed:
  • Hanxiao Zhang

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Chenyu Zhou

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Zarith Mohammad

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Jianhua Zhao

    (Sanford Burnham Prebys Medical Discovery Institute)

Abstract

New proteasomes are produced to accommodate increases in cellular catabolic demand and prevent the accumulation of cytotoxic proteins. Formation of the proteasomal 20S core complex relies on the function of the five chaperones PAC1-4 and POMP. Here, to understand how these chaperones facilitate proteasome assembly, we tagged the endogenous chaperones using CRISPR/Cas gene editing and examined the chaperone-bound complexes by cryo-EM. We observe an early α-ring intermediate subcomplex that is stabilized by PAC1-4, which transitions to β-ring assembly upon dissociation of PAC3/PAC4 and rearrangement of the PAC1 N-terminal tail. Completion of the β-ring and dimerization of half-proteasomes repositions critical lysine K33 to trigger cleavage of the β pro-peptides, leading to the concerted dissociation of POMP and PAC1/PAC2 to yield mature 20S proteasomes. This study reveals structural insights into critical points along the assembly pathway of the human proteasome and provides a molecular blueprint for 20S biogenesis.

Suggested Citation

  • Hanxiao Zhang & Chenyu Zhou & Zarith Mohammad & Jianhua Zhao, 2024. "Structural basis of human 20S proteasome biogenesis," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52513-0
    DOI: 10.1038/s41467-024-52513-0
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    References listed on IDEAS

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    1. Malte Kock & Maria M. Nunes & Matthias Hemann & Sebastian Kube & R. Jürgen Dohmen & Franz Herzog & Paula C. Ramos & Petra Wendler, 2015. "Proteasome assembly from 15S precursors involves major conformational changes and recycling of the Pba1–Pba2 chaperone," Nature Communications, Nature, vol. 6(1), pages 1-10, May.
    2. Adrien Rousseau & Anne Bertolotti, 2016. "An evolutionarily conserved pathway controls proteasome homeostasis," Nature, Nature, vol. 536(7615), pages 184-189, August.
    3. Yuko Hirano & Klavs B. Hendil & Hideki Yashiroda & Shun-ichiro Iemura & Ryoichi Nagane & Yusaku Hioki & Tohru Natsume & Keiji Tanaka & Shigeo Murata, 2005. "A heterodimeric complex that promotes the assembly of mammalian 20S proteasomes," Nature, Nature, vol. 437(7063), pages 1381-1385, October.
    4. David Vilchez & Isabel Saez & Andrew Dillin, 2014. "The role of protein clearance mechanisms in organismal ageing and age-related diseases," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
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